The fundamental objective of the proposed research is to establish a basic level of knowledge concerning the detailed molecular structure of the enzyme dihydrofolate reductase. It is expected that this enzyme's structural variability from species to species will provide a basis for rational development of species specific chemotherapeutic drugs. We expect to solve the X-ray crystal structure of a chicken liver dihydrofolate reductase: NADPH binary complex. Mechanism arguments and a rationalization of inhibitor binding will be developed based on: (1) structural comparison between E. coli, L. casei and chicken liver dihydrofolate reductases and (2) small molecule binding to chicken liver dihydrofolate reductase using the powerful difference Fourier technique.